Several aspects of histamine disposition in mammalian brain resemble that of other biogenic amines, such as norepinephrine, dopamine and serotonin. Histamine is distributed unevenly throughout the brain with the highest levels in the hypothalamus. Subcellular fractionation of brain tissue indicates that a major portion of brain histamine released from synaptosomes by shock tends to localize in a fraction enriched in synaptic vesicles. To my knowledge, no one has previously demonstrated a unique uptake system for the precursor of histamine, histidine. The hypothesis is that histidine is taken up into histaminergic nerve endings by a high affinity (low Km value) transport mechanism and that the availability of histamine at the synapse is dependent upon the transport of its precursor, histidine. Independent variables will be metabolic inhibitors, radio-frequency lesions, and drug treatment. Dependent variables will be the amount of 3H-histadine transported, metabolized and released as histamine in brain synaptosomes. The methodological approach includes in vitro uptake of 3H-L-histidine into brain synaptosomes. Metabolism of histidine to histamine will be evaluated by high-voltage electrophoresis. The understanding of detailed aspects of precursor availability and histamine biosynthesis, release, and receptor binding may help in the elucidation of the mechanism of action of numerous psychotropic drugs as well as aid in the development of new and novel therapeutic agents.